The proposed program is directed at a total synthesis of a wide range of biologically active medium-sized carbocylic and heterocyclic natural products. Our objective includes the development of general synthetic methods which would allow the preparation of natural products and their synthetic derivatives in significant quantities for biological testing. The new synthetic methods include (1) the (4 + 3] cycloadditions of cyclic oxyallyls (i.e., the oxyallyl functionality is embedded in a ring) and heteratom-substituted oxyallyls;(2) the tandem applications of the diastereoselective hydroxycyclopropanation and the oxy-Cope rearrangement or free-radical ring closure; (3) the furan-mediated annulation and subsequent furan to cyclopentenone rearrangement. Specific target molecules include ingenol (1a) and/or phorbol (2a) which are potent cocarcinogenic diterpenes; ophiobolins (4) which show interesting inhibitory activities of Ca2+-binding calmodulins or angiotensin II receptor binding; colchicine (6)which binds to tublin and thus offers potent antimitotic activities; and furanoheliangolide sesquiterpenes (9- 14), some of which have been shown to exhibit significant levels of in vitro antitumor activity. Concurrent with these new foci, we will also bring to a successful conclusion several ongoing research projects involving the development of general, practical syntheses of structurally diverse bioactive natural products. The target compounds include alpha-pyrone polyene mycotoxins of the citreoviridin family, which are potent inhibitors of oxidative phospho; erythromycin A which is a representative member of clinically important macrolide antibiotics; bioactive alkaloids such as polyhydroxy indolizidine alkaloids and their glycoconjugates, clavepictines, and gephrotoxin, which have shown antitumor activity or provided invaluable tools for the investigation of ion transport in many biological systems; and allene oxide-derived prostanoids whose biogenesis has fascinating evolutionary implications.